Introduction: PTEN is a tumor suppressor frequently deleted in prostate cancer that may be a useful prognostic biomarker. However, the association of PTEN loss with lethal disease has not been tested in a large, predominantly surgically-treated cohort. Moreover, PTEN loss is more common in TMPRSS2:ERG gene fusion-positive tumors, compared to fusion-negative tumors. Thus, presence of TMPRSS2:ERG gene fusion may modify the effects of PTEN loss on disease progression. We conducted a large patho-epidemiology investigation among prostate cancer patients in the Health Professional Follow-up Study and the Physicians’ Health Study addressing: 1) the association of PTEN loss, assessed by a validated IHC protocol, with lethal progression, and 2) the potential for TMPRSS2:ERG gene fusion, detected by IHC, to modify the role of PTEN loss in lethal disease progression.

Methods: In the Health Professionals Follow-Up Study and Physicians’ Health Study, we followed 1045 incident prostate cancer cases diagnosed between 1986 - 2009 for cancer and all-cause mortality. A genetically validated PTEN immunohistochemistry (IHC) assay was performed on tissue microarrays (TMA). TMPRSS2:ERG status was previously assessed in a subset of cases by a genetically validated IHC assay for ERG. Cox proportional hazards models adjusting for age and BMI at diagnosis, Gleason grade, and clinical or pathologic TNM stage were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) of the association with lethal disease.

Results: On average men were followed 11.6 years, during which there were 82 lethal events. 16% of cases had complete PTEN loss in all TMA cores and 9% had heterogeneous PTEN loss in a subset of cores. Men whose tumors showed complete PTEN loss had a significantly higher risk for lethal progression compared to men whose tumors showed PTEN intact or heterogeneous loss, even after adjusting for clinical-pathologic characteristics (HR = 1.9; 95% CI = 1.2-3.0). The association of PTEN loss (complete or heterogeneous) with lethal progression was only among men with ERG negative (HR = 2.8; 95% CI = 1.5-5.2), but not ERG positive (HR = 1.2; 95% CI = 0.6-2.2) tumors.

Conclusions: PTEN loss is independently associated with increased risk of lethal progression, particularly in the ERG fusion negative subgroup. These validated and inexpensive IHC assays may be useful for risk stratification in prostate cancer.

Citation Format: Thomas U. Ahearn, Andreas Pettersson, Ericka M. Ebot, Travis Gerke, Carlos De Morais, Jessica Hicks, Kathryn M. Wilson, Jennifer R. Rider, Michelangelo Fiorentino, Stephen Finn, Edward L. Giovannucci, Massimo Loda, Meir J. Stampfer, Angelo M. De Marzo, Lorelei A. Mucci, Tamara L. Lotan. A prospective investigation of PTEN loss and ERG expression in lethal prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 939. doi:10.1158/1538-7445.AM2015-939